During the development of T-cells, lymphoid stem cells migrate into the thymic rudiment where they proliferate, rearrange their antigen receptor genes, are selected in regard to their MHC-specificity repertoire and differentiate into functionally mature T cells (Refs. 1-6). Prothymocytes having the cell surface marker phenotype CD7.sup.+ CD2.sup.- CD3.sup.- represent the earliest identifiable step in T cell lineage (Refs. 7-10). Recent in vitro findings (Refs. 8-11) pointed to the ability of these prothymocytes to acquire mature T cell surface markers following appropriate conditioning. The cellular and factor mediated interactions for this process are poorly understood. A role for cytokines such as IL-1 (Ref. 12) and IL-2 (Ref. 11) was suggested. The ability of IL-1 to function as hemopoietin-1 and to induce development of multipotent hemopoietic cells if it is combined with colony stimulating factors, such as GM-CSF, G-CSF, CSF-1, IL-3, erythropoietin, or erythroid-potentiating activity, is disclosed in the PCT application WO88/00969.
B cells are implied to produce various lymphokines which can intervene in T cell differentiation (Refs. 15, 16). The ability of supernatants derived from PHA induced "B+null" cells (peripheral blood lymphocytes depleted from adherent and mature T cells) to promote in vitro the generation of mature T cell clones from prothymocytes regardless of their anatomical origins was reported (Refs. 8, 13, 14). This prothymocyte differentiating activity (PTDA) was B cell derived (Ref. 14). IL-1 alone had no effect in this respect. However, "B+null" cell-derived supernatants with PTDA always contained low IL-1 levels, whereas neither IL-2, IL-3, IL-4, IL-5, IL-6, GM-CSF, TNF nor IFN-.gamma. were detected in these supernatants (Refs. 8, 14). Biological activities of "B+null" cell-derived supernatants are e.g. the ability to promote the formation of cells able to generate T colony from mature T cell depleted bone marrow, thymus and PBL, the capacity to enhance CD4.sup.+ cell derived responses, the ability to increase CFU-GM, CFU-GEMM, and BFU-E numbers in Dexter cultures, the ability to increase the formation of myeloid colonies in cultures of bone marrow cells from patients with refractory anemia, and the ability to induce mature T cell markers on cells derived from some acute lymphoblastic leukemias with prothymocyte features. An example of such an acute lymphoblastic leukemia with prothymocyte features in which the tumor cells have a CD7.sup.+ CD4.sup.- CD8.sup.- phenotype was described by Kurtzberg et al. (Ref. 10).
Compounds with PTDA may be useful in the treatment of such leukemias, because the mature T cells derived from the leukemia cells with prothymocyte features may have lost tumorigenicty.
T cell immunodeficiencies can be caused by the incapability of the organism to produce mature T cells or by the loss of mature T cells. T cell immunodeficiences occur e.g. in patients with thymic dysfunctions, after immunosuppressive therapy, in elderly and AIDS patients.
Compounds with PTDA may be useful in the treatment of such T cell immunodeficiencies.